Substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles of formula (I) are useful
as inhibitors of gastric acid secretion.wherein R1, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, and halogen; R4-R7 are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, and trifluoroalkyl.
For example, the compounds with generic names omeprazole, lansoprazole, rabeprazole, pantoprazole are used in the treatment of peptic ulcer. These compounds have a chiral center at the sulphur atom and thus exist as two optical isomers, i.e. enantiomers.
It has been well recognized in several pharmacologically active compounds that one of the enantiomer has superior biological property compared to the racemate and the other isomer.
For example, omeprazole (CAS Registry No. 73590-58-6), chemically known as 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl}-1H-benzimidazole, is a highly potent inhibitor of gastric acid secretion. It has a chiral center at the sulphur atom and exists as two enantiomers (S)-(−)-omeprazole and (R)-(+)-omeprazole. It has been shown that the (S)-enantiomer of omeprazole has better pharmacokinetic and metabolic properties compared to omeprazole. The (S)-enantiomer of omeprazole having generic name esomeprazole is marketed by Astra Zeneca in the form of magnesium salt under the brand name NEXIUM®. Therefore, there is a demand and need for an industrial scale process for manufacturing esomeprazole.
The methods of synthesis of racemic sulphoxide compounds of formula (I) are very successful for a large-scale industrial manufacture. However, the production of optically pure sulphoxide compounds of formula (I) is not easy.
The prior art methodologies for the preparation of single enantiomers of sulphoxides of formula (I) are based on enantioselective or chiral synthesis, optical resolution of the racemate, separation by converting the racemate to diastereomers, or by chromatography.
For example, some of the earliest prior art on enantioselective synthesis of the single enantiomers of sulphoxides of formula (I) described in Euro. J. Biochem. 166, (1987), 453, employed asymmetric sulphide oxidation process developed and reported by Kagan and co-workers in J. Am. Chem. Soc. 106 (1984), 8188. The process disclosed therein provides sulphoxide products in an enantiomeric excess of only about 30%, which upon several recrystallization steps yielded optically pure sulphoxide up to an e.e. of 95%. The oxidation was performed by using tert-butyl hydroperoxide as oxidizing agent in the presence of one equivalent of a chiral complex obtained from Ti(OiPr)4/(+) or (−)-diethyl tartrate/water in the molar ratio of 1:2:1. A minimum of 0.5 equivalent of titanium reagent was found to be a must for obtaining very high enantioselectivity.
An improvement in the above oxidation process to obtain higher enantioselectivity was reported by Kagan and co-workers in Tetrahedron (1987), 43, 5135; wherein tert-butyl hydroperoxide was replaced by cumene hydroperoxide. In their further study reported in Synlett (1990), 643; Kagan and co-workers found that high enantioselectivity can be obtained if the temperature is maintained between −20° C. to −40° C., and methylene chloride is used as a solvent.
In contrary to Kagan's observation of requirement of low temperature and chlorinated solvent like methylene chloride for high enantioselectivity of the chiral oxidation, Larsson et al in U.S. Pat. No. 5,948,789 (equivalent to PCT publication WO 96/02535) have described an enantioselective process for the synthesis of the single enantiomers of compound of formula (I) by the chiral oxidation of the pro-chiral sulphide of formula (Ia) utilizing a chiral titanium (IV) isopropoxide complex in solvent systems such as toluene, ethyl acetate at 20-40° C., and most importantly a base like amine such as triethyl amine or diisopropyl amine.

Although the formation of % e.e. of the desired isomer is satisfactory, the method suffers from the disadvantage (a) of low chemical conversion; (b) formation of undesired sulphide and sulfone impurities in substantial amounts, necessitating further purification by one or more tedious crystallization.
It is obvious from the above that such conversions which result in low chemical conversion and require costly metal complex and protracted purification, surely, is not desirable process for making a product such as optically active prazole in an industrial scale.
WO 96/17076 teaches a method of enantioselective biooxidation of the sulphide compound (Ia), which is effected by the action of Penicillium frequentans, Brevibacterium paraffinolyticum or Mycobacterium sp.
WO 96/1707 teaches the bioreduction of the racemic omeprazole to an enantiomer or enantiomerically enriched sulphide of formula (Ia), which is effected by the action of Proteus vulgaris, Proteus mirabilis, Escherichia coli, Rhodobacter capsulatus or a DMSO reductase isolated from R. capsulatus. 
The separation of enantiomers of omeprazole in analytical scale is described in Marie et al.; J. Chromatography, 532, (1990), 305-19. WO 03/051867 describes a method for preparation of an enantiomerically pure or optically enriched enantiomer of either omeprazole, pantoprazole, lansoprazole, or raberpazole from a mixture containing the same using means for simulated moving bed chromatography with a chiral stationary phase such as amylose tris(S)-methylbenzycarbanmate. However, chromatographic methods are not suitable for large-scale manufacture of these prazoles.
The optical resolution methods taught in the art for separating the enantiomers of certain 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles of formula (I) utilizes the diastereomer method, the crystallization method or the enzyme method.
The resolution process disclosed in DE 4035455 and WO 94/27988 involve converting the racemate 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles to a diastereomeric mixture using a chiral acyl group, such as mandeloyl, and the diastereomers are separated and the separated diastereomer is converted to the optically pure sulphoxide by hydrolysis.
The method suffers from the following disadvantages,                (i) the resolution process involves additional steps of separation of diastereomeric mixture, and hydrolysis of the N-substituent in separated diastereomer,        (ii) the conversion of the racemate to diastereomeric acyl derivative is low yielding (˜40%),        (iii) the diastereomer from the unwanted (R)-enantiomer is separated and discarded,WO 2004/002982 teaches a method for preparation of optically pure or optically enriched isomers of omeprazole by reacting the mixture of optical isomers with a chelating agent (D)-diethyl tartrate and transition metal complex titanium (IV) isopropoxide to form a titanium metal complex in an organic solvent such as acetone in presence of a base such as triethyl amine, which is then converted to salt of L-mandelic acid. The mandelic acid salt of the titanium complex of optical isomer derived from (S)-enantiomer of omeprazole gets precipitated, which is separated and purified to obtain chiral purity of about 99.8%.        
Optically active 1,1′-bi-2-naphthol (BINOL) and its derivatives are useful as chiral ligands in catalysts for asymmetric reactions to hosts for molecular recognition and enantiomer separation, and often intermediates for the synthesis of chiral molecules.
BINOL is known to form crystalline complexes with a variety of organic molecules through hydrogen bonding. The (S) and/or (R) BINOL was found to be useful as a chiral host for enantioselective complexation. The application of BINOL in resolution of omeprazole is disclosed Deng et al in CN 1223262.
The Chinese patent application CN 1223262 (Deng et al) teaches the utility of chiral host compounds such as dinaphthalenephenols (BINOL), diphenanthrenols or tartaric acid derivatives in the resolution of prazoles. The method consists of formation of 1:1 solid complex between the chiral host and one of the enantiomer of the prazole, the guest molecule. The other enantiomer remains in the solution. The racemic prazole is treated with the chiral host in a mixture of solvent comprising of aromatic hydrocarbon solvents such as benzene, alkyl substituted benzene or acetonitrile and, hexane. The solid complex is separated from the solution, and dissolved again in afresh solvent system by heating to 60-130° C. and then keeping at −20-10° C. for 6-36 hrs to obtain higher e.e. value for the solid complex. The process is repeated many times to obtain high e.e. values for the solid complex. The host and the guest in the solid complex are separated by column chromatography. The final separated single enantiomer of the prazole is then recrystallized from a mixture of methylene chloride or chloroform and, ether.
In a later publication in Tetrahedron Asymmetry 11 (2000), 1729-1732 the inventors of the above mentioned Chinese patent application reported the resolution of omeprazole using (S)-BINOL. An inclusion complex of (S)-BINOL and (S)-omeprazole was obtained as a grey-blue complex with 90.3% e.e. by mixing racemate omeprazole and (S)-(−)-BINOL in the mole ratio 1:1.5, in a solvent mixture of benzene:hexane (v/v=4:1) at 110° C. The inclusion complex obtained was further purified by recrystallization in benzene:hexane (v/v, 1:1) and separated on a silica gel column to yield (S)-(−)-omeprazole with 98.9% e.e. and 84.1% overall yield. The (S)-(−)-omeprazole so obtained was recrystallized in water to obtain as a white powder with 99.2% e.e.
In this publication, the authors have reported their observation of criticality of the benzene:hexane solvent ratio in obtaining the inclusion complex and the enantioselectivity. The authors reportedly have obtained the best enantioselectivity of 90.3% e.e. when the solvent ratio of benzene:hexane is 4:1 and the mole ratio of racemate omeprazole and (S)-(−)-BINOL is 1:1.5.
Further, by comparing the IR stretching frequencies observed for S═O bond in racemate omeprazole (1018 cm−1) and its inclusion complex with (S)-(−)-BINOL (1028 cm−1), the authors have concluded that the S═O bond which involved in a N—H . . . O═S hydrogen bond does not attribute the formation of hydrogen bonding in the inclusion complex, and the chiral recognition in the inclusion complex may occur via formation of hydrogen-bonded supramolecular chiron.
The method described in the above-mentioned Chinese patent application suffers in that,                (i) due to very low e.e. value for the solid complex obtained for the first time, the complexation process has to be repeated till the desired e.e. value is obtained,        (ii) to separate the host and the guest, one has to take recourse to tedious chromatographic methods,        (iii) overall the resolution involves several operations of complex formation, separation, purification by chromatography and recrystallization,        (iv) For the purpose of chromatography the amount silica and the solvent required is exorbitant        (v) with more operation steps, there is considerable material loss leading to lowering of the overall yield, which is not satisfactory for a commercial scale production,        (vi) the use of hexane with low flash point is not recommended for industrial processes,        (vii) volumes of the solvents to be handled having low flash point are quite large, necessitating special design of plant and machinery for safety,        (viii) benzene is carcinogenic and is listed as a class 1 solvent in ICH guideline.        
Taking these considerations, the process disclosed in the CN 1223262 (Deng et al) does not give cost effective and eco-friendly method of manufacture.
It is evident from the above that there is a need for synthesizing optically pure sulphoxide compounds of formula (I), their salts, and their hydrates by a process that is (a) cost effective (b) simple (c) easy to operate (d) eco-friendly, (e) consistently give good yields and purity with minimum variables (e) highly reproducible.
The present invention provides such a solution.